Abstract
In this study we compared the efficacy of 1000 mg phenazone with that of placebo in the treatment of acute migraine attacks in a randomized double-blind, placebo-controlled study of 208 patients. The main target criterion was the number of patients with a pain reduction from severe or moderate to slight or no pain 2 h after taking the pain medication. The percentage of patients satisfying the main target criterion was 48.6% for phenazone and 27.2% (P < 0.05) for placebo. Freedom from pain after 2 h was reported by 27.6% with phenazone treatment and 13.6% (P < 0.05) with placebo. Compared with placebo, the phenazone treatment also resulted in a significant improvement in the associated migraine symptoms of nausea, phonophobia and photophobia. Of patients treated with phenazone 11.4%, and 5.8% of those treated with placebo reported adverse events. There was no significant difference between the groups with regard to numbers of patients with adverse events. No serious adverse events occurred. The results show that phenazone at a dosage of 1000 mg is effective and well tolerated in the treatment of acute migraine attacks.
Introduction
For decades, drugs containing phenazone have been used in the treatment of acute migraine attacks and other pain problems (1–4). Despite this long and frequent use there has to date been no controlled study of the efficacy and tolerability of phenazone in the treatment of acute migraine attacks.
Phenazone is absorbed quickly and completely in the gastrointestinal tract. Following administration of 1000 mg phenazone, maximum saliva concentrations have been observed after as little as 60 min. The plasma concentration curve is comparable, with periods of 1–2 h being reported for t max(2–8). This rapid initial increase in the plasma concentration is particularly advantageous for the treatment of acute migraine attacks.
In this study the efficacy of phenazone 1000 mg in a new rapid-release tablet in the treatment of acute migraine attacks was investigated and compared with the efficacy of placebo treatment. The effect on the associated migraine symptoms of nausea, vomiting, photophobia, phonophobia and disability was also investigated for the first time.
Patients and methods
Ethics
The clinical study was conducted in accordance with the 1996 revision of the Helsinki Declaration and in compliance with the local laws and regulations. The study protocol was approved by the Ethics Committee of the University of Kiel. The patients signed declarations of consent and confirmed that they fully understood the purpose of the study, the planned methods, and the possible benefits and risks of participation in the study.
Patients
Men or women aged 18–65 years were invited to take part in the study if they satisfied the criteria for migraine with or without aura for at least 12 months in accordance with the first edition of the headache classification of the International Headache Society. Attack frequency had to be between one and six attacks per month, and the patients had to be able to identify a migraine attack. The exclusion criteria included other headache syndromes requiring medication therapy, migraine aura without headache, migraine with prolonged aura, familial hemiplegic migraine, basilar migraine, known hypersensitivity to the study medication, known hypersensitivity to pyrazolone and phenylbutazone, known genetic glucose-6-phosphate-dehydrogenase deficiency, acute intermittent porphyria, and other significant neurological or other disorders. Other exclusion criteria were pregnancy, breast feeding, psychological disorders, medication or alcohol abuse, and participation in another study in the 4 weeks preceding the screening appointment or during the course of the study.
Design and methods
The study was conducted as a double-blind, placebo-controlled, monocentric study of parallel-group design. It compared the efficacy, safety and tolerance of oral phenazone 1000 mg and placebo in treating one migraine attack. A total of 240 patients were randomized in the ratio 1 : 1 (120 per treatment group, intention-to-treat sample). Complete data are available for 208 patients (per protocol sample), of whom 105 were treated with phenazone 1000 mg and 103 with placebo. The patients were recruited in the Pain Clinic's out-patient department from May 2002 to December 2002. The study medication consisted of two 500-mg tablets of phenazone in a newly developed rapid-release form, or placebo tablets of identical appearance. The patients were instructed to take their study medication as soon as possible within 4 h of the onset of a typical migraine headache. The migraine headache had to be of at least moderate intensity. The patients were not allowed to have taken any other migraine arrest medication within 24 h before taking the study medication. The patients had to keep a headache diary that documented the migraine symptoms for a period of 24 h. The migraine attacks were not to be already easing off spontaneously at the time of taking the medication. If the study medication proved ineffective, the patients were allowed to take rescue medication of their own choice at any time after taking the study medication, but were asked to do so 2 h after taking the study medication, if possible. The patients were requested to document their migraine symptoms in a headache diary at baseline, after 30, 60, 90 and 120 min, and after 3, 4, 5, 6 and 24 h.
A complete record of the previous medical history and accompanying medication and a physical and neurological examination were made during the initial consultation. A pregnancy test was also carried out, and the study medication was not allowed to be taken if a pregnancy test was positive.
The randomization of the subjects to form the study groups was by means of a computer-generated method. The randomization list was provided by the sponsor, as well as the numbered blister packs containing either phenazone or corresponding placebo tablets. The investigator was only allowed to circumvent the blinding system in emergency by opening emergency envelopes. The sponsor did not release the randomization code until the study had been completed.
Efficacy parameters
The subjects documented the intensity of the acute migraine attack in a headache diary. This was based on a four-point scale: 0, no pain; 1, slight pain; 2, moderate pain; 3, severe pain. The main target criterion was defined as the number of patients with a pain reduction from severe or moderate pain to slight or no pain 2 h after taking the study medication. Repeat headache was defined as a return of the headache to moderate or severe intensity within 2–24 h, if the patients exhibited an initial response within 2 h after taking the study medication. Secondary efficacy parameters included the frequency of patients with any pain intensity reduction within 2 h, the frequency of patients reporting freedom from pain within 2 h, the frequency of patients with an improvement in associated symptoms (nausea, vomiting, phonophobia, photophobia) within 2 h, the frequency of repeat headaches within 24 h, the global rating of the therapy by the patients 24 h after taking the medication, the time until rescue medication was taken, the frequency of incapacity for school or work 24 h after taking the medication, the frequency of a productivity reduction of at least 50%, and the frequency of adverse events.
Recording of tolerability
ECG, pulse and blood pressure measurements were taken during the first visit. All adverse events, whether relating to the study medication or not, were recorded in structured lists (symptom, beginning and end, severity, frequency, possible treatment, outcome). A physical examination and pulse and blood pressure measurements were made at the final visit. The patients were asked about adverse events. Details of the accompanying medication were recorded, the headache diaries were returned and discussed with the patients.
Power calculation and statistical analysis
The primary main target parameter was defined as the number of patients with a pain reduction from severe or moderate to slight or no pain 2 h after taking the study medication. Assuming a response rate of 30% in the placebo group and 50% in the phenazone group, i.e. a clinically relevant difference of 20%, a total of 103 patients per treatment group are required for a power of 1 − β= 80%. This was based on Fisher's exact test and a significance level of α= 5% (two-tailed). Thus a total of 206 patients were to complete the study. All analyses were performed on the intention-to-treat (ITT) population, defined as all randomized patients who took the study medication with a valid baseline and at least one post-baseline evaluation. The secondary target criteria were subjected to exploratory statistical analysis. Statistical significance was defined as P < 0.05.
Results
Patients
A total of 240 patients were randomized, 120 patients for treatment with phenazone 1000 mg and 120 patients for treatment with placebo. There were no differences between the treatment groups with regard to gender, age, age on commencement of migraine syndromes, duration of migraine syndrome, migraine subgroups, blood pressure, heart rate, height and weight (Table 1).
Patient demographics
One hundred and five patients treated a migraine attack with phenazone and 103 patients treated a migraine attack with placebo. There were no differences between the two groups with regard to migraine attack symptoms at baseline, whether for headache intensity, nausea, vomiting, photophobia, phonophobia or for migraine-induced disability (Table 2).
Headache severity and associated symptoms at baseline
Efficacy
Main target criterion
The main target criterion was defined as the number of patients with a pain reduction from severe or moderate pain to slight or no pain 2 h after taking the study medication. The responder rate was 48.6% (51/105) under phenazone and 27.2% (28/103) under placebo (Fig. 1). The difference is significant: χ2(1) = 10.1; P = 0.002 (two-tailed, Fisher's exact test).
Pain reduction from severe/moderate to slight/no pain 2 h after intake of the study medication (phenazone n = 105, placebo n = 103).
For patients with initially moderate pain (n = 69 for phenazone and n = 68 for placebo), the responder rate was 53.6% (37/69) under phenazone and 32.4% (22/68) under placebo, with significant difference: χ2(1) = 6.3; P = 0.016. However, for patients with initially severe pain (n = 36 for phenazone and n = 35 for placebo), the response rate was lower in both groups [38.9% (14/36) under phenazone and 17.1% (6/35) under placebo]. This difference was also significant: χ2(1) = 4.1; P = 0.042.
Secondary target criteria
The number of patients free from pain within 2 h was 27.6% (n = 29/105) in the phenazone group and 13.6% (14/103) in the placebo group (Fig. 2). The difference is significant: χ2(1) = 6.2; P = 0.016.
No. of patients with pain-free response within 2 h after intake of the study medication (phenazone n = 105, placebo n = 103).
The number of patients with any reduction in pain intensity within 2 h was 54.3% (57/105) in the phenazone group and 32.0% (33/103) for placebo. The difference is significant: χ2(1) = 10.5; P = 0.001.
Significant differences were found between the groups with regard to improvements in associated symptoms within 2 h: photophobia (33.7% phenazone, 18.9% placebo), phonophobia (42.5% phenazone, 18.6% placebo) and nausea (55.1% phenazone, 29.9% placebo). Vomiting was on the whole infrequent in both groups. Significant differences between the groups were found for photophobia, phonophobia and nausea (Table 3).
Improvement of associated symptoms within 2 h after intake of the study medication
Of the patients in the phenazone group, 21.0% rated the global efficacy of the study medication very good, 14.3% good, 17.1% average and 47.6% poor. The corresponding figures for the placebo group were 11.7% (very good), 4.9% (good), 10.7% (average) and 72.8% (poor). The difference in distribution between the groups was significant in favour of the phenazone group: χ2(1) = 14.6; P = 0.002.
Two hours after taking the study medication, 38.1% of the patients in the phenazone group and 69.9% of the patients in the placebo group took rescue medication. The difference in distribution was significant: χ2(1) = 18.5; P < 0.001. The time until rescue medication was taken after the study medication was not significantly different (2 h 12 min ± 46 min phenazone, 1 h 56 min ± 46 min placebo). Only nine patients (n = 1 for phenazone and n = 8 for placebo) took rescue medication after they had taken the study medication in a period of < 2 h. Excluding these nine patients from analyses, the responder rates and the main target criterion changed only marginally to 49.0% (51/104) for phenazone and 28.4% (27/95) for placebo. The difference is significant: χ2(1) = 8.9; P = 0.004.
Of the patients treated with phenazone, 25.7% reported a recurrence headache, while the figure for placebo was 16.5%. The difference was not significant.
The number of patients unfit for school or work 24 h after taking the study medication was 23.8% in the phenazone group and 35.0% in the placebo group. The difference was not significant.
The number of patients with at least a 50% productivity reduction 24 h after taking the study medication was 69.5% in the phenazone group and 59.2% in the placebo group. The difference was not significant.
Tolerability
Based on the ITT sample, 12 patients (10.0%) in the group treated with phenazone recorded a total of 13 adverse events (tiredness n = 3, muscular weakness n = 1, diarrhoea n = 1, dry mouth n = 1, stomach ache n = 1, bitter taste n = 2, throat pains n = 1, increase in headache n = 1, nausea n = 1, vomiting n = 1). The adverse events were generally of moderate intensity and displayed spontaneous remission. No serious adverse events (SAE) occurred.
In the group treated with placebo, six patients (5.0%) recorded a total of six adverse events (vomiting n = 2, stomach pains n = 2, tiredness n = 1, vertigo n = 1). The adverse events were also generally of moderate intensity and displayed spontaneous remission. No SAEs occurred. There was no significant difference between the groups with regard to numbers of patients with adverse events.
Discussion
While there is a wide variety of literature on the various options for therapy of acute migraine attacks (9–12), the efficacy and tolerability of phenazone have not yet been investigated in a controlled study. This study showed 1000 mg phenazone to be effective and well tolerated in the treatment of acute migraine attacks. The 2-h response rates for phenazone were significantly superior to those of placebo. The incidence of freedom from pain after 2 h was also higher after treatment with phenazone than with placebo. Phenazone also resulted in a significant improvement in the associated symptoms of nausea, phonophobia and photophobia, and proved to be well tolerated in the treatment of attacks.
The 2-h response rates are comparable to those of the standard analgesic acetylsalicylic acid (ASA) in combination with metoclopramide (between 43 and 57%) (13–17). Comparative studies have hitherto failed to demonstrate any clear superiority of the 2-h response rates for triptans compared with analgesics such as ASA, ketoprofen, diclofenac-K or tolfenamic acid (13). However, most triptans display larger numerical values for efficacy parameters than those found here for phenazone. It is particularly interesting to note that phenazone possesses a much more favourable side-effects profile than non-steroidal anti-inflammatory drugs, and that the restrictions on the use of the latter, such as chronic or recurrent gastric and duodenal problems or simultaneous therapy with anticoagulant drugs, are not relevant.
Pharmaceuticals containing phenazone have been used for years to treat migraine and headaches. More recent studies have indicated the existence of a central action mechanism. It is particularly interesting that phenazone reduces pontine and cortical 5-HT binding sites (8, 18, 19). Phenazon is absorbed quickly and completely in the gastrointestinal tract (2–8). Following administration of 1000 mg phenazone, maximum saliva concentrations have been observed after as little as 60 min. The plasma concentration curve is comparable, periods of 1–2 h being reported for t max. A rapid initial increase in the plasma concentration is particularly advantageous for the treatment of acute migraine attacks. For the first time, this study used a rapid-release form that supports this effect. Phenazone is generally well tolerated. Although it has been in use for decades, no undesirable effects on haemogenesis have been described for phenazone, unlike other members of the pyrazolone family.
In summary, the results show that phenazone 1000 mg is very well tolerated and brings about fast and effective alleviation of migraine pains and associated symptoms.
Footnotes
Acknowledgements
The authors thank Krewel-Meuselbach Pharmaceuticals (Eitorf, Germany) for supporting this research.